biorxiv2026-10-12score 91
Alexander disease astrocytes uncouple the glycerol-3-phosphate shuttle to keep cytosolic NAD+ when the electron transport chain fails
van Gelder, Hol, Burgering and colleagues separate GFAP dose from the Alexander disease mutation R239C with single-cell proteomics. High wild-type GFAP starts to look like R239C, so accumulation matters, but the mutant specifically raises mitochondrial antioxidant enzymes and retunes the proteasome toward ATP- and ubiquitin-independent disposal of oxidized proteins. Patient cortical organoids add nuclear-encoded mitochondrial proteins and respiratory assembly factors without a matching rise in mitochondrially encoded subunits, which they read as impaired electron transport chain assembly. AxD cells then drop oxygen consumption, raise glycolysis, lean on the cytosolic arm of the glycerol-3-phosphate shuttle, and store triacylglycerides. The named couple is NAD+/NADH: partial G3P-shuttle uncoupling regenerates cytosolic NAD+ so glycolysis can run without sending those reducing equivalents fully into the Q pool. The abstract does not name GPD2, FAD, or which respiratory complex fails assembly.
